四溴联苯醚BDE47是最重要的PBDEs之一，其代谢产物与甲状腺素结构非常相似，可能通过甲状腺素干扰效应导致发育毒性，而DNA甲基化被认为与环境因素密切相关的表观遗传学机制。CYP3A4是人体代谢环境污染物最主要的代谢酶，我们发现：BDE47可通过诱导CYP3A表达并增加其活性代谢产物而使其毒效应增强。为此，本研究在构建斑马鱼CYP3A65(与人CYP3A4同源)敲除模型的基础上，通过研究CYP3A65的时空表达谱、CYP3A65与BDE47原位代谢的相关性、BDE47暴露窗口期与斑马鱼发育异常表型、甲状腺素稳态及功能相关基因甲基化状态及调控靶点，从代谢酶调控与表达、生物转化、发育异常及表观遗传学机制等环节，以新的视角系统审视BDE47的生物转化及其引起发育异常的过程及机制，为预防PBDEs的生殖发育危害、保护人群健康提供重要参考，也为化学物的毒性评价与风险评估提供新的研究策略。

2,2',4,4'-tetrabromodiphenyl ether (BDE47) is one of the most important dominant PBDE congeners, the structures of its metabolites are much similar to thyroid hormone, possibly inducing the developmental toxicity through disrupting thyroid hormone homeostasis. Besides, DNA methylation is one of the most important modifications involved in environmental exposure in epigenetics. Cytochrome P450 3A4 (CYP3A4) plays a very important role in the metabolism of xenobiotics. Our previous study had shown that BDE47 significantly increased the expression and activity of CYP3A1 in rat live whilst CYP3A1 mediated metabolic activation of BDE47. To explore the role of CYP3A65 (homologous to human CYP3A4) in BDE47-induced the developmental toxicity, CYP3A65 knockout zebrafish will be constructed. The spatial and temporal expression of CYP3A65, which may mediate the metabolism of BDE47 in situ, will be investigated using this model. In addition, the relationship between dysplasia phenotype in zebrafish and window period of BDE47 exposure will be explored. The methylation of thyroid hormone and related genes will be analyzed to reveal the underlying molecular mechanism. The purpose of this study is to explore expression and regulation of metabolic enzymes, biotransformation, dysplasia and possible epigenetic mechanisms. The results will help provide insights into the metabolism of BDE47 and the subsequent dysplasia, and give novel clues to the prevention and control of environmental pollutant-induced biological damages, supply a new strategy for toxicity evaluation and risk assessment as well.